NEW ORLEANSThe monoclonal antibody tositumomab (Bexxar) showed
promising efficacy in low-grade and follicular non-Hodgkins
lymphoma in several preliminary studies reported during poster
presentations at the ASH meeting.
Julie M. Vose, MD, of the University of Nebraska in Omaha reported
that both naked tositumomab and tositumomab linked to iodine 131 are
safe and effective for treating patients with low-grade follicular
lymphoma. Dr. Vose analyzed data from five phase I/II studies
including 179 patients with follicular small cleaved cell or
follicular mixed cell with greater than 50% small cleaved cell
histology at the time of treatment.
Infusions Well Tolerated
Most patients had received a single dosimetric dose of 450 mg of
tositumomab IV over 1 hour followed by 35 mg of tositumomab
radiolabeled with 5 mCi of iodine 131 over 12 hours. Whole-body gamma
camera counts were then obtained over the next week. These were used
to calculate the required activity (mCi) to deliver the desired
therapeutic dose (65 cGy for platelets 100,000 to 149,999
cells/mm³ and 75 cGy for platelets >150,000 cells/mm³).
About 7 to 14 days after the dosimetric dose, patients received a
single therapeutic dose of 450 mg of tositumomab followed by 35 mg of
tositumomab containing an appropriate activity of iodine 131 to give
the total body dose.
Dr. Vose reported that responses were observed in 145/179 (81%) of
patients and that 69/179(39%) had complete responses (CR). The median
duration of response was 11 months, and the mean duration of complete
response was 57 months.
Tositumomab and iodine-131 tositumomab produced an overall
response in 74 patients with relapsed follicular small-cleaved and in
75% of patients with relapsed follicular mixed cell NHL, Dr.
Vose said. Infusions were well tolerated, with infusion rate
adjustments required in only 7% of the dosimetric infusions and 2% of
the therapeutic dose infusions. Median hematologic toxicity nadirs
occurred 32 to 45 days after therapy and were reversible. Overall,
only 19% of patients required hematologic support.
Previously untreated patients were more likely to develop
human-anti-murine antibodies (HAMA). Dr. Vose said that only 11% of
patients previously treated with chemotherapy developed HAMA.
Used With Fludarabine
John P. Leonard, MD, of Weill Medical College of Cornell University
and New York Presbyterian Hospital, New York, reported preliminary
data showing that fludarabine (Fludara) and iodine-131 tositumomab
can be given safely as a combination regimen and that the
immunosuppressive effect of fludarabine appears to suppress HAMA
response to tositumomab and I-131 tositumomab in patients with
previously untreated low-grade or follicular NHL.
This study involved 38 patients, including 14 evaluable for response
at the time of this report. All patients received 3 cycles of
fludarabine (25 mg/m² for 5 days every 5 weeks). Patients then
received oral iodine for thyroid blockade and a single dosimetric
dose of 450 mg of tositumomab IV over 1 hour followed by 35 mg (5
mCi) of I-131 tositumomab over 20 minutes.
Whole-body gamma counts were used to calculate the therapeutic dose,
which was given 7 to 14 days after the dosimetric dose. Patients were
given trimethoprim-sulfamethoxazole to prevent pneumocystis carinii pneumonia.
The efficacy of tositumomab and I-131 tositumomab appears to
augment that of fludarabine improving overall and complete responses,
with 100% of patients achieving a response, Dr. Leonard
reported (see Table 1).
Only one patient developed HAMA, and the researchers concluded that
the immunosuppressive effects of fludarabine limit seroconversion to
HAMA. Toxicity following fludarabine was mainly hematologic. The
principal toxicity following combination treatment was also
hematologic, with 5/15 patients (36%) having an absolute neutrophil
count (ANC) nadir of less than 500 cells/mm3 and 1/14 (7%) having a
platelet nadir under 10,000 cells/mm³.
Relapsed or Refractory NHL
Stephanie A. Gregory, MD, of Rush Cancer Institute in Chicago
reported preliminary data showing that tositumomab can be safely
administered to patients with relapsed or refractory low-grade or
transformed low-grade NHL who have been previously treated with
rituximab (Rituxan). All 30 patients in an expanded access study had
previously received rituximab. They were then treated with dosimetric
and then therapeutic doses of tositumomab and iodine 131 tositumomab.
Hematologic toxicities included ANC nadir less than 500 cells/mm³
in 5 (18%) patients, platelet nadir less than 10,000 cells/mm³
in 1 (4%), and hemoglobin nadir less than 6.5 g/dL in 1 (4%). One
patient had febrile neutropenia possibly related to treatment.